Three tachykinins, Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are widely distributed throughout the peripheral and central nervous systems. The biological effects of these neuropeptides are primary mediated via binding to and subsequent activation of the three neurokinin receptors, NK1, NK2 and NK3. Substance P is considered to be the endogenous ligand for the NK1 receptor and likewise NKA and NKB for the NK2 and NK3 receptors, respectively. However, recent data indicates that there exist cross-reactivity within the tachykinin system, which might be of physiological relevance as both NKA and NKB potently are able to bind and activate the NK1 receptor (for review see Maggi, C A et al: Trends Pharmacol Sci. 1997, 18, p 351-5). The three receptor subtypes belong to the G-protein-coupled receptor super family and have been cloned in various species including mice, rats and humans (Nakanishi S: Annu Rev Neurosci. 1991, 14, p 123-36).
The three tachykinin receptors are expressed both centrally and in the periphery. The NK3 receptor is mainly expressed centrally in regions including cortex, striatum, substantia nigra compacta, ventral tegmental area, hypothalamus, amygdala and hippocampus (Stroessl A J et al: Brain Res. 1990, 534, p 1-7, Koutcherov Y et al: Neuroreport. 2000, 11, p 3127-31). In the periphery, the NK3 receptor is expressed in regions including colon, kidney, lungs and the urinary bladder (Regoli D et al: Trends Pharmacol Sci. 1988 August; 9(8): 290-5, Kamali F: Curr Opin Investig Drugs. 2001 July; 2(7):950-6). Centrally, the NK3 receptor is expressed on cholinergic (Chen L W et al: Neuroscience. 2001; 103(2):413-22), noradrenergic (references within Oury-Donat F et al: J. Pharmacol Exp Ther. 1995, 274, p 148-54) and dopaminergic neurons (Keegan K D et al: Br. J. Pharmacol. 1992, 105, p 3-5). In agreement with these results, activation of the NK3 receptor has been reported to be implicated in the regulation of various monoamine transmitters, e.g. dopamine and acetylcholine (Marco N et al: Neuropeptides. 1998, 32, p 481-8, Stoessl A J et al: Brain Res. 1990, 517, p 111-6), noradrenaline (Jung M et al: Neuroscience. 1996, 74, p 403-14) and serotonine (Stoessl A J et al: Brain Res. 1990, 517, p 111-6).
The NK3 receptor-mediated regulation of monoamine systems supports that the NK3 receptor is involved in diverse functions including memory, learning, cortical processing and behavioral control (Yip J et al: Br J Pharmacol. 1997, 122, p 715-25, Ding Y Q et al: J Comp Neurol. 1996, 364, p 290-310, Mileusnic D et al: Neurobiol Aging. 1999, 20, p 19-35) and that it is target for various psychological and neurological disorders (Emonds-Alt X et al: Can J Physiol Pharmacol. 2002, 80, p 482-8, Kamali F, Curr Opin Investig Drugs. 2001, 2, p 950-6, Langlois X et al: J Pharmacol Exp Ther. 2001, 299, p 712-7). Indeed, the NK3 receptor has been reported to be implicated in modulation of anxiety (Ribeiro S J et al: Neuropeptides. 1999, 33, p 181-8).
Further, it has been reported that the NK3 receptor antagonist SR142801 has effect against schizophrenia, in particular positive symptoms. SR142801 is described in, e.g., EP 673928. The structure of SR142801 is outlined below (Kamali F: Curr Opin Investig Drugs. 2001, July; 2(7):950-6).

In vivo, NK3 receptor activation centrally has been reported to mediate hypertension and tachycardia (Nagashima A et al: Brain Res. 487, 1989, p 392-396, Takano Y et al: Brain Res. 1990, 528, p 231-7, Picard P et al: Br J Pharmacol. 1994, 112, p 240-9) whereas NK3 receptor activation in the periphery mediates hypotension and bradycardia (Couture R et al: Naunyn Schmiedebergs Arch Pharmacol. 1989, 340, p 547-57). Additional in vivo studies have indicated that NK3 receptor activation decrease water, salt and alcohol intake (Massi M et al: Brain Res Bull. 1991 26 p155-60, Massi M et al: Neurosci Lett. 1988, 92, p 341-6 and Ciccocioppo R et al: Brain Res Bull. 1994, 33, p 71-7) which together with the localization of the NK3 receptor on MCH neurons support a role of the NK3 receptor in the regulation of food intake (Griffond B et al: J Chem Neuroanat. 1997, 12, p 183-9). Further in vivo studies have shown that the NK3 receptor is implicated in renal control of water and electrolyte homeostasis (Yuan Y D: Br J Pharmacol. 1997, 120, p 785-96). Activation of the NK3 receptor has been reported to inhibit gastric acid secretion (Improta G et al: Peptides. 1991, 12, p 1433-4), induce oral dyskinesia (Liminga U et al: Pharmacol Biochem Behav. 1991, 38, p 617-20) and oedema (Inoue H et al: Inflamm Res. 1996, 45, p 316-23).
In vitro NK3 activation has been reported to have proconvulsive effect (Maubach K A et al: Neuroscience. 1998, 83, p 1047-62) and to mediate hyperexcitability in ischemic injury (Stumm R et al: J Neurosci. 2001, 21, p 798-811).
Selective high affinity non-peptide NK3 receptor antagonists have been shown to be antinociceptic (Fioramonti J et al: Neurogastroenterol Motil. 2003, 15, p 363-9, Couture R et al: Life Sci. 2000, 66, p 51-65, Julia V et al: Gastroenterology. 1999, 116, p 1124-31, Coudore-Civiale M A: European Journal of Pharmacology 1998, 361, p 175-184) and analgesic (Houghton A K et al: Neuropharmacology. 2000, 39, p 133-40). In addition, studies demonstrate consistent effect of a NK3 receptor antagonist against visceral pain encouragingly precluding constipation (Mayer E A et al: Gastroenterology. 1999, 116, p1250-2, Julia V et al: Gastroenterology. 1999 116 p124-31). Similarly inhibition of the NK3 receptor is stated to prevent gut inflammation highlighting effect against inflammatory bowel disease (Mazelin L et al: Life Sci. 1998, 63, p 293-304), cough, airway hyperresponsiveness, microvascular hypersensitivity and reduction of bronchoconstriction (Daoui S et al: Am J Respir Crit Care Med. 1998, 158, p 42-8, Rumsey W L et al: J Pharmacol Exp Ther. 2001, 298, p 307-15, Daoui S et al: Pulm Pharmacol Ther. 1997 10 p261-70). Inhibition of the NK3 receptor as therapeutic strategy for Parkinsons disease has been substantiated in several reports (Arenas E: J Neurosci. 1991, 11, p 2332-8, Kernel M L et al: J Neurosci. 2002, 22, p 1929-36).
Accordingly, pre-clinical, in vivo and in vitro studies support that NK3 receptor antagonists are of relevance for the treatment or prevention of various disorders including: schizophrenia, depression, anxiety, Parkinson's disease, pain, convulsions, cough, asthma, airway hyperresponsiveness, microvascular hypersensitivity, bronchoconstriction, gut inflammation, inflammatory bowel disease, hypertension, imbalances in water and electrolyte homeostasis, ischemia, oedema and plasma extravasation.
Hence, there is a desire for NK3 receptor antagonists. The present inventors have now found such compounds with a strong affinity for the NK3 receptor.
Several patent applications relate to compounds disclosed as NK receptor antagonist, e.g. EP 474561, EP 512901 and WO 03/051869. In particular, some patent applications relate to compounds disclosed as NK3 receptor antagonist, e.g. WO 9710211, U.S. Pat. No. 5,434,158 and EP 673928. U.S. Pat. No. 5,750,549 disclose cyclopentane derivatives as NK1 receptor antagonist.
The compounds of the present invention are all cyclopropyl derivates. As described in the following, some patent applications relate to different cyclopropane derivatives. However, none of these patent applications relates to the NK3 receptor or others of the NK receptors.
JP 03056415 describes cyclopropane derivatives of the following formula
for treatment of cerebral ischemia.
EP 68999 describes cyclopropane derivatives of the following formula
for treatment of depression.